國(guó)家自然基金申請(qǐng)書寫作：ceRNA與腫瘤的發(fā)生發(fā)展

ceRNA對(duì)腫瘤的調(diào)控基于20多年對(duì)microRNA的相關(guān)研究，我們已了解到這類長(zhǎng)度僅包含17-25個(gè)核苷酸的內(nèi)源性非編碼RNA作為轉(zhuǎn)錄后調(diào)控因子廣泛參與機(jī)體的發(fā)育、分化以及新陳代謝等生理過(guò)程，其在生命周期的基因調(diào)控網(wǎng)絡(luò)中發(fā)揮著重要的作用ADDINEN.CITEADDINEN.CITE.DATA\o"Alvarez-Garcia,2005#5"1,\o"Wang,2016#6"2。同時(shí)發(fā)現(xiàn)，microRNA在進(jìn)化上高度保守，一種microRNA可通過(guò)與靶基因mRNA3’UTR區(qū)域的MRE識(shí)別并誘導(dǎo)基因沉默復(fù)合物RISC的裝配，進(jìn)而調(diào)控多個(gè)靶基因的活性或穩(wěn)定性，且多種microRNA也可協(xié)同調(diào)控同一個(gè)靶基因。由此設(shè)想，共享有同一種microRNAMRE序列的不同基因轉(zhuǎn)錄物間構(gòu)成了競(jìng)爭(zhēng)，他們對(duì)同種microRNA的結(jié)合此消彼長(zhǎng)，從而形成復(fù)雜的RNA調(diào)控網(wǎng)絡(luò)，既調(diào)節(jié)各自的表達(dá)水平又相互影響，最終影響細(xì)胞的命運(yùn)，即為ceRNA假說(shuō)\o"Salmena,2011#7"ADDINEN.CITE<EndNote><Cite><Author>Salmena</Author><Year>2011</Year><RecNum>7</RecNum><DisplayText><styleface="superscript">3</style></DisplayText><record><rec-number>7</rec-number><foreign-keys><keyapp="EN"db-id="ssdftpwx8efex3edxa8v59st9552a5zwz9ee">7</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Salmena,L.</author><author>Poliseno,L.</author><author>Tay,Y.</author><author>Kats,L.</author><author>Pandolfi,P.P.</author></authors></contributors><auth-address>CancerGeneticsProgram,BethIsraelDeaconessCancerCenter,DepartmentsofMedicineandPathology,BethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,MA02215,USA.</auth-address><titles><title>AceRNAhypothesis:theRosettaStoneofahiddenRNAlanguage?</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>353-8</pages><volume>146</volume><number>3</number><edition>2011/08/02</edition><keywords><keyword>Animals</keyword><keyword>*GeneExpressionProfiling</keyword><keyword>GeneExpressionRegulation</keyword><keyword>Humans</keyword><keyword>MicroRNAs/genetics</keyword><keyword>Neoplasms/genetics/metabolism</keyword><keyword>Pseudogenes</keyword><keyword>RNA/*genetics/*metabolism</keyword><keyword>RNA,Messenger/genetics</keyword><keyword>RNA,Untranslated/genetics</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug5</date></pub-dates></dates><isbn>1097-4172(Electronic) 0092-8674(Linking)</isbn><accession-num>21802130</accession-num><urls><related-urls><url>/pubmed/21802130</url></related-urls></urls><custom2>3235919</custom2><electronic-resource-num>10.1016/j.cell.2011.07.014 S0092-8674(11)00812-9[pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>3。其中，共享有相同MRE又構(gòu)成競(jìng)爭(zhēng)關(guān)系的不同轉(zhuǎn)錄物統(tǒng)稱為競(jìng)爭(zhēng)性內(nèi)源RNA（completingendogenousRNA，ceRNA），包括編碼蛋白的mRNA、長(zhǎng)鏈非編碼RNA（lncRNA）、假基因轉(zhuǎn)錄本以及環(huán)狀RNA（circRNA）等\o"Tay,2014#8"ADDINEN.CITEADDINEN.CITE.DATA4。該假說(shuō)先后通過(guò)生物信息學(xué)、細(xì)胞生物學(xué)等實(shí)驗(yàn)得到了驗(yàn)證，向我們展示了全新的轉(zhuǎn)錄組調(diào)控網(wǎng)絡(luò)ADDINEN.CITEADDINEN.CITE.DATA\o"Tay,2011#9"5,\o"Poliseno,2010#10"6。普遍認(rèn)為，精準(zhǔn)的基因表達(dá)調(diào)控對(duì)機(jī)體的穩(wěn)態(tài)維持和正常的生理活動(dòng)至關(guān)重要，而RNAs調(diào)控網(wǎng)絡(luò)的異常是誘發(fā)多種疾病的主要因素。ceRNA的提出進(jìn)一步完善了人類對(duì)轉(zhuǎn)錄組和RNA調(diào)控網(wǎng)絡(luò)的認(rèn)知，為探究多種疾病的發(fā)生發(fā)展提供了全新的視野。研究表明，惡性腫瘤細(xì)胞中的ceRNAs能夠與原癌基因、抑癌基因以及多種腫瘤相關(guān)信號(hào)通路因子的mRNA3’UTR區(qū)域的MRE競(jìng)爭(zhēng)性結(jié)合靶向microRNA，從而促進(jìn)或抑制microRNA的相關(guān)功能，在腫瘤的發(fā)生、惡化、侵襲、轉(zhuǎn)移甚至藥物治療中發(fā)揮著重要作用\o"Karreth,2013#11"ADDINEN.CITEADDINEN.CITE.DATA7-10。例如通過(guò)對(duì)TCGA數(shù)據(jù)庫(kù)中的惡性膠質(zhì)瘤的基因表達(dá)譜分析發(fā)現(xiàn)，約有7000多種基因的轉(zhuǎn)錄物之間以ceRNA的方式相互聯(lián)系和影響，其中涉及PTEN、視網(wǎng)膜母細(xì)胞瘤1（RB1）、VEGF-A、STAT3等腫瘤相關(guān)基因\o"Sumazin,2011#16"ADDINEN.CITE<EndNote><Cite><Author>Sumazin</Author><Year>2011</Year><RecNum>16</RecNum><DisplayText><styleface="superscript">11</style></DisplayText><record><rec-number>16</rec-number><foreign-keys><keyapp="EN"db-id="ssdftpwx8efex3edxa8v59st9552a5zwz9ee">16</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Sumazin,P.</author><author>Yang,X.</author><author>Chiu,H.S.</author><author>Chung,W.J.</author><author>Iyer,A.</author><author>Llobet-Navas,D.</author><author>Rajbhandari,P.</author><author>Bansal,M.</author><author>Guarnieri,P.</author><author>Silva,J.</author><author>Califano,A.</author></authors></contributors><auth-address>ColumbiaInitiativeinSystemsBiology,ColumbiaUniversity,NewYork,NY10032,USA.</auth-address><titles><title>AnextensivemicroRNA-mediatednetworkofRNA-RNAinteractionsregulatesestablishedoncogenicpathwaysinglioblastoma</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>370-81</pages><volume>147</volume><number>2</number><edition>2011/10/18</edition><keywords><keyword>*GeneExpressionRegulation,Neoplastic</keyword><keyword>Glioblastoma/*genetics/*metabolism</keyword><keyword>Humans</keyword><keyword>MicroRNAs/*metabolism</keyword><keyword>MultivariateAnalysis</keyword><keyword>Oncogenes</keyword><keyword>PTENPhosphohydrolase/genetics</keyword><keyword>RNAInterference</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct14</date></pub-dates></dates><isbn>1097-4172(Electronic) 0092-8674(Linking)</isbn><accession-num>22000015</accession-num><urls><related-urls><url>/pubmed/22000015</url></related-urls></urls><custom2>3214599</custom2><electronic-resource-num>10.1016/j.cell.2011.09.041 S0092-8674(11)01152-4[pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>11；Poliseno等發(fā)現(xiàn)，前列腺癌細(xì)胞中的假基因PTENP1轉(zhuǎn)錄本可通過(guò)競(jìng)爭(zhēng)性結(jié)合miR-19b、miR-20a、miR-214等多種靶向PTEN的microRNA，提高PTEN的表達(dá)水平從而抑制PI3K/Akt信號(hào)通路的激活，最終抑制腫瘤細(xì)胞的增殖，相反，PTENP1表達(dá)的抑制伴隨著PTEN表達(dá)的下調(diào)和腫瘤細(xì)胞增殖水平的提高\(yùn)o"Poliseno,2010#10"ADDINEN.CITEADDINEN.CITE.DATA6；同樣在肝癌相關(guān)的研究中發(fā)現(xiàn)，versicanmRNA的3’UTR競(jìng)爭(zhēng)性結(jié)合miR-144、miR-133a等，且假基因OCT4-pg4的轉(zhuǎn)錄本可解除miR-145對(duì)OCT4的抑制，從而促進(jìn)腫瘤細(xì)胞的增殖、遷移和侵襲能力，抑制細(xì)胞凋亡的發(fā)生ADDINEN.CITEADDINEN.CITE.DATA\o"Fang,2013#17"12,\o"Wang,2013#18"13。對(duì)腫瘤相關(guān)ceRNA研究的不斷豐富和深入，不僅將有助于揭示和完善腫瘤發(fā)生和發(fā)展事件背后的分子機(jī)制，而且其可作為新型的生物標(biāo)記分子和潛在的藥物靶點(diǎn)用于腫瘤的臨床診治和預(yù)后評(píng)估ADDINEN.CITEADDINEN.CITE.DATA\o"Shao,2015#19"14,\o"Sanchez-Mejias,2015#20"15。參考文獻(xiàn)ADDINEN.REFLIST1. 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